Creatine Shows Promise for Depression but Evidence Remains Mixed

Creatine is one of the most popular supplements in the world, used primarily to enhance muscle strength and athletic performance. Now, scientists are asking whether it could also support mental health — specifically by helping the brain generate energy more efficiently in people with depression.

A new systematic review published in Brain Medicine examined five randomized controlled trials, covering 238 participants across South Korea, the United States, Brazil, Israel, and India. Participants averaged 36 years of age, and most were women. Researchers from the University of Ottawa evaluated each trial individually rather than pooling data, because the studies differed too much in design to be combined statistically.

The results were split. Two trials — both involving women with major depressive disorder — reported meaningful benefits. In one, women taking five grams of creatine daily alongside the antidepressant escitalopram showed significantly greater symptom reduction after eight weeks, with a Cohen's d of 1.13 on the Hamilton Depression Rating Scale — a large effect by conventional standards. A second study pairing creatine with cognitive behavioral therapy also showed superior symptom reduction compared to therapy plus placebo.

However, three other trials found no measurable benefit. One tested creatine in treatment-resistant depression; another examined adolescent girls at varying doses; a third enrolled patients with bipolar disorder in a depressive episode. None showed improvement over placebo.

The biological rationale is plausible: depression has been linked to disrupted brain energy metabolism, and creatine plays a key role in cellular energy production. But inconsistency across trials — in populations, doses, and co-treatments — makes it impossible to draw firm conclusions yet. Sex-based differences in creatine metabolism may partly explain why results were positive only in female participants.

For now, creatine remains a supplement with potential, not a proven antidepressant. Larger, more targeted trials are needed before clinical recommendations can be made.